Protein Health Research Articles

Identification of the Regulatory Region of the Peripheral Myelin Protein 22 (PMP22) Gene That Directs Temporal and Spatial Expression in Development and Regeneration of Peripheral Nerves

Minor changes in PMP22 gene dosage have profound effects on the development and maintenance of peripheral nerves. This is evident from the genetic disease mechanisms in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) as well as transgenic animals with altered PMP22 gene dosage. Thus, regulation of PMP22 is a crucial aspect in understanding the function of this protein in health and disease. In this study, we have generated transgenic mice containing 10 kb of the 5′-flanking region of the PMP22 gene, including the two previously identified alternative promoters, fused to a lacZ reporter gene. We show that this part of the PMP22 gene contains the necessary information to mirror the endogenous expression pattern in peripheral nerves during development and regeneration and in mouse models of demyelination due to genetic lesions. Transgene expression is strongly regulated during myelination, demyelination, and remyelination in Schwann cells, demonstrating the crucial influence of neuron–Schwann cell interactions in the regulation of PMP22. In addition, the region of the PMP22 gene present on this transgene confers also neuronal expression in sensory and motor neurons. These results provide the crucial basis for further dissection of the elements that direct the temporal and spatial regulation of the PMP22 gene and to elucidate the molecular basis of the master program regulating peripheral nerve myelination.

Ubiquitin-mediated degradation of cellular proteins in health and disease

HepatologyVolume 35, Issue 1 p. 3-6 Science FrontierFree Access Ubiquitin-mediated degradation of cellular proteins in health and disease Aaron Ciechanover M.D., Ph.D., Corresponding Author Aaron Ciechanover M.D., Ph.D. c_tzachy@netvision.net.il mdaaron@tx.technion.ac.il Department of Biochemistry, The Bruce Rappaport Faculty of Medicine and the Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Biochemistry, Faculty of Medicine, Technion-Israel Institute of Technology, Efron Street, Bat Galim, Haifa 31096, Israel. fax: (972) 4-851-3922.===Search for more papers by this authorAlan L. Schwartz, Alan L. Schwartz Departments of Pediatrics and Molecular Biology and Pharmacology, St. Louis Children' Hospital and Washington University School of Medicine, St. Louis, MOSearch for more papers by this author Aaron Ciechanover M.D., Ph.D., Corresponding Author Aaron Ciechanover M.D., Ph.D. c_tzachy@netvision.net.il mdaaron@tx.technion.ac.il Department of Biochemistry, The Bruce Rappaport Faculty of Medicine and the Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Biochemistry, Faculty of Medicine, Technion-Israel Institute of Technology, Efron Street, Bat Galim, Haifa 31096, Israel. fax: (972) 4-851-3922.===Search for more papers by this authorAlan L. Schwartz, Alan L. Schwartz Departments of Pediatrics and Molecular Biology and Pharmacology, St. Louis Children' Hospital and Washington University School of Medicine, St. Louis, MOSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2002.30316Citations: 55AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume35, Issue1January 2002Pages 3-6 ReferencesRelatedInformation

Computing power

Case Western Reserve University (Cleveland, OH, USA) has received a US$ 2.2 million grant from the Charles B. Wang Foundation to establish the Center for Computational Genomics, where researchers will analyse the function of genes and proteins in health and disease. Wang is the founder and chairman of Computer Associates (Islandia, NY, USA), the fourth largest software company in the world. The center will be the home of an interdisciplinary research and training program, tackling cutting-edge problems in genomics and bioinformatics.

Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.

Folding and bioassembly of secretory proteins in health and disease

Folding and bioassembly of secretory proteins in health and disease

Glycoprotein structure determination by mass spectrometry.

The human genome encodes 30,000 to 40,000 proteins, and a major challenge is to understand how posttranslational events, such as glycosylation, affect the activities and functions of these proteins in health and disease. Glycosylated proteins are ubiquitous components of extracellular matrices and cellular surfaces where their oligosaccharide moieties are implicated in a wide range of cell-cell and cell-matrix recognition events. The power of ultrahigh-sensitivity mass spectrometric strategies for defining the primary structures of highly complex mixtures of glycoprotein glycoforms is set to revolutionize structural glycobiology in the coming postgenomic era.

New Insights into the Role of Nuclear Factor-κB, a Ubiquitous Transcription Factor in the Initiation of Diseases

Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that governs the expression of genes encoding cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-kappaB is activated by several agents, including cytokines, oxidant free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappaB has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappaB has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. Therefore, development of modulatory strategies targeting this transcription factor may provide a novel therapeutic tool for the treatment or prevention of various diseases.

Anion exchangers in the red cell and beyond

The anion exchanger genes (AE1-3) encode a family of transport proteins responsible for the electroneutral exchange of bicarbonate and chloride across membranes. These transporters are important in processes such as pH regulation and bicarbonate metabolism. This article reviews recent progress in this field based on presentations made at a satellite workshop on anion exchangers held in conjunction with the 8th Fisher Winternational Symposium on Cellular and Molecular Biology entitled "Membrane proteins in health and disease." The transmembrane topology of AE1 has been refined using various combinations of protein chemistry and site-directed mutagenesis. The use of specific inhibitors and novel expression systems continues to reveal fundamental features of the anion exchanger mechanism and its regulation. The importance of anion exchangers in blood and kidney diseases is underscored by the identification and characterization of a plethora of novel mutations in the AE1 gene. Investigations of anion exchanger structure and function have moved beyond studies of the red cell protein into the larger arenas of cellular and molecular biology.Key words: anion exchanger, band 3, erythrocyte, membrane protein, pH regulation.

Anion exchangers in the red cell and beyond.

The anion exchanger genes (AE1-3) encode a family of transport proteins responsible for the electroneutral exchange of bicarbonate and chloride across membranes. These transporters are important in processes such as pH regulation and bicarbonate metabolism. This article reviews recent progress in this field based on presentations made at a satellite workshop on anion exchangers held in conjunction with the 8th Fisher Winternational Symposium on Cellular and Molecular Biology entitled "Membrane proteins in health and disease." The transmembrane topology of AE1 has been refined using various combinations of protein chemistry and site-directed mutagenesis. The use of specific inhibitors and novel expression systems continues to reveal fundamental features of the anion exchanger mechanism and its regulation. The importance of anion exchangers in blood and kidney diseases is underscored by the identification and characterization of a plethora of novel mutations in the AE1 gene. Investigations of anion exchanger structure and function have moved beyond studies of the red cell protein into the larger arenas of cellular and molecular biology.

The Distribution of Essential Trace Elements amongst the Plasma Proteins in Health and Disease

The Distribution of Essential Trace Elements amongst the Plasma Proteins in Health and Disease

Changes in glycosylation of acute-phase proteins in health and disease: Occurrence, regulation and function

The pathophysiological variations in different glycoforms of acute-phase glycoproteins in serum most likely result from changes in the glycosylation process during their biosynthesis in the parenchymal cells of the liver. Biosynthesis in other cells or tissues may contribute, but in general appears to play a minor role. Inflammatory cytokines appear to regulate the process, but glycosylation changes are independent of protein synthesis. In addition, other humoral factors such as corticosteroids and growth factors are involved. The interplay of these factors is determined by the stage of the disease (e.g rheumatoid arthritis), the physiological situation (e.g. pregnancy), or directly or indirectly by extraneous factors such as drugs (e.g. ethanol). Information about the functional implications of the changes is limited, but some reports suggest that for α1-acid glycoprotein the changes might affect the operation of the immune system.

Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease.

Plasma and whole-body turnover studies of human C-reactive protein (CRP), isolated from a single normal healthy donor and labeled with 125I, were undertaken in 8 healthy control subjects and 35 hospitalized patients including cases of rheumatoid arthritis, systemic lupus erythematosus, infections, and neoplasia. Plasma clearance of 125I-CRP closely approximated to a monoexponential function and was similar in the control and all patient groups. There was no evidence for accelerated clearance or catabolism of CRP in any of the diseases studied. The 19-h half-life was more rapid than that of most human plasma proteins studied previously, and the fractional catabolic rate was independent of the plasma CRP concentration. The synthesis rate of CRP is thus the only significant determinant of its plasma level, confirming the validity of serum CRP measurement as an objective index of disease activity in disorders associated with an acute-phase response. Approximately 90% of injected radioactivity was recovered in the urine after 7 d, and scintigraphic imaging studies with 123I-labeled CRP in 10 patients with different focal pathology showed no significant localization of tracer. The functions of CRP are thus likely to be effected predominantly in the fluid phase rather than by major deposition at sites of tissue damage or inflammation.

Heat shock proteins in health and disease.

Heat shock proteins are among the most abundant proteins of the biosphere. They not only play a major role under stress conditions but also perform important physiological functions. The present review summarizes the potential contribution of heat shock proteins to health and disease related to immunity: their contribution to antibody assembly and antigen presentation; their role in host cell protection against "immune stress"; their participation in tumor surveillance; their relation to gamma/delta T-cell recognition; their function as microbial virulence factors; their dominant antigenicity for the immune response against microbial pathogens; and their possible role as autoantigens. The findings summarized here illustrate the marked liaison between heat shock proteins and the immune response, which may be both beneficial and detrimental to the host.

The van Cittert-Zernike theorem in pulsed ultrasound: Implications for speckle reduction: Raul Mallart and Mathias Fink, Laboratoire Ondes et Acoustique, Université Paris 7/ESPCI, 10 Rue Vauquelin, 75005 Paris, France

Genetic disease mechanisms in the demyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1A (CMTA) and hereditary neuropathy with liability to pressure palsies (HNPP) as well as transgenic animals with altered PMP22 gene dosage revealed that alterations in PMP22 gene expression have profound effects on the development and maintenance of peripheral nerves. Consequently, the regulation of PMP22 is a crucial aspect in understanding the function of this protein in health and disease. In this study, we dissected and analyzed different cis-acting elements in the 5′-flanking region of the Pmp22 gene in vivo. We found two separate elements that contribute to different aspects of Pmp22 expression. The first is located 5′ distally to promoter 1 and is involved in gene regulation during late phases of myelination in development [“late myelination Schwann cell-specific element” (LMSE)] and in remyelination after injury. The second element was identified upstream of promoter 2 and guides Pmp22 expression in sensory neurons. These results suggest that multiple distinct signaling pathways regulating Pmp22 expression in myelination as well as in neurons converge on distinct segments of the PMP22 promoter region. The underlying molecular mechanisms are likely to be crucially involved in the maintenance of the integrity of myelinated peripheral nerves.

Structure of the Extracellular Matrix in Normal and Fibrotic Liver: Collagens and Glycoproteins

The sketches in Figures 11 and 12, necessarily simplified, summarize some of the points discussed in the previous paragraphs. It can be concluded that the hepatic ECM and the ECM in general is a complicated supramolecular assembly of numerous defined macromolecules, each of which is endowed with a specific potential for interactions with one another and with various cell types. This matrix not only adapts rapidly to slight metabolic changes of the cells producing it, but also itself modulates the biochemical and morphologic phenotype of the cells anchored to it. Since mesenchymal cells appear to be the major source of hepatic ECM proteins in health and disease, it follows that the mesenchyme determines to a significant degree the phenotype of liver epithelial cells. Based on the growing knowledge of the hepatic ECM, immunoassays for ECM proteins or peptides in serum may provide information about the dynamics of fibrogenesis or fibrolysis in individual patients on a day to day basis, or permit detection of derangements of the hepatic ECM before they become clinically apparent. The clinical value of such assays is already being studied. Finally, knowing the molecules and the cells involved in ECM pathologic states offers us the tools to develop a specific targeted antifibrogenic therapy.

Regulation of plasma growth hormone-binding proteins in health and disease

Binding proteins (BP) for growth hormone (GH) have recently been discovered in human plasma. The main BP is related to the GH receptor and probably corresponds to the extracellular portion of the receptor. The BP influence several aspects of GH homeostasis and action. Their level and activity in blood, therefore, become important variables in overall GH physiology. However, to date little is known about the regulation of GH-BP in health and disease. To gain initial information about this point, GH-BP activity was examined in the plasma of 124 subjects with various physiologic and pathologic conditions. The conditions were selected to provide basic physiologic data (men, women, children, age, pregnancy) and to investigate key disease states attended by abnormal GH physiology (liver cirrhosis, uremia, infection, acromegaly). A standardized GH binding assay was used to measure BP activity as an index of BP levels. Both the principal, high affinity BP (peak II) and the minor, low affinity BP (peak I) showed considerable individual variation in all groups. Neonates had the lowest levels of both BPs, but by the age of 1 year the levels had increased and remained fairly stable through the seventh decade. In males but not females between the ages of 1 and 20 years, the main (peak II) BP showed a slight upward trend, whereas the minor (peak I) BP declined moderately. Patients with cirrhosis showed the most variation in both BP, and uremic patients demonstrated decreased peak II, but not peak I, binding. Neither BP was affected in acromogaly. We conclude that BP activity in plasma is well conserved in most conditions, but substantial individual variability exists. BP activity increases dramatically during the first year of life. The two BPs appear to be differently regulated, with peak I, but not peak II, showing evidence for sex hormone dependence. The high affinity (peak II) BP carries 80% to 90% of the complexed GH. We propose to define one unit of BP activity as that contained in 1 mL of normal adult plasma. Under the conditions of analysis used in this report, one unit corresponds to a bound GH fraction of 30%.

Serum amyloid A protein (SAA) in horses: objective measurement of the acute phase response

A sensitive and precise immunoassay for equine serum amyloid A protein (SAA) was established and used to determine, for the first time, the circulating concentration of this protein in health and disease. As in other species, equine SAA was present only at trace levels in healthy animals but behaved as an extremely sensitive and rapidly responding acute phase reactant following most forms of tissue injury, infection and inflammation, objectively reflecting the extent and activity of disease. Measurements of SAA should make a significant contribution to diagnosis and management of viral and bacterial infection in horses, and routine serial assays could provide an objective criterion for monitoring prospectively the general health of horses in training and racing.

Fifth International Symposium of Nephrology at Montecatini Kidney and Proteins in Health and Disease

Journal Article Fifth International Symposium of Nephrology at Montecatini Kidney and Proteins in Health and Disease Get access Endocrinology, Volume 119, Issue 4, 1 October 1986, Page 1602, https://doi.org/10.1210/endo-119-4-1602 Published: 01 October 1986

Studies of thyroxine binding to plasma proteins in health and disease

Thyroxine binding protein characteristics were defined in 6 normal subjects, 4 with thyroxine binding globulin (TBG) deficiency, 3 with TBG increase, one with hyperthyroxinemic dysalbuminemia, 7 with severe non-thyroidal illness, and 3 with chronic renal failure. Free thyroxine was measured by Sephadex partition in plasma to which increasing thyroxine concentrations were added. Deconvolution of the resultant titration data was performed by computer modelling. Abnormalities of thyroxine binding capacities or of binding affinities occur in non-thyroidal illness, chronic renal failure, and sporadically. The patient with hyperthyroxinemic dysalbuminemia had increased thyroxine binding affinity to thyroxine binding prealbumin as well as to albumin. "Free-T4 assays" or estimates of Free-T4 by calculation from total thyroxine and measures of protein binding such as T3-uptake must be expected to be perturbed by these binding protein abnormalities unless such interferences are explicitly demonstrated to be absent.

Immunohistochemical Studies of Amyloid P Component Distribution in Normal Human Skin

The distribution of amyloid P component (AP) in normal human skin was investigated by a light and electron microscopic immunoperoxidase technique, using antibodies to serum amyloid P component (SAP). AP, or an immunologically cross-reactive protein, was found to be specifically localized to the microfibrils of papillary oxytalan fibers and to the peripheral microfibrillar mantle surrounding the elastin core of mature elastic fibers in the reticular dermis; collagen fibers were not stained with anti-SAP. AP was not detected in the dermal-epidermal basement membrane or in the basement membranes surrounding dermal papillary blood vessels and eccrine structures. These findings, which establish the detailed distribution of normal tissue AP in the skin, provide a basis for further studies of the function and behavior of this protein in health and disease.